High DLL4 expression in tumour-associated vessels predicts for favorable radiotherapy outcome in locally advanced squamo
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ORIGINAL PAPER
High DLL4 expression in tumour-associated vessels predicts for favorable radiotherapy outcome in locally advanced squamous cell head-neck cancer (HNSCC) Michael I. Koukourakis • Alexandra Giatromanolaki Efthimios Sivridis • Kevin C. Gatter • Adrian L. Harris
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Received: 28 July 2012 / Accepted: 16 October 2012 / Published online: 30 October 2012 Ó Springer Science+Business Media Dordrecht 2012
Abstract Introduction Expression of the DLL4 (a notch pathway ligand) by tumor-associated endothelium is a postulated marker of vascular maturity and functionality. As vascular functionality is an important parameter defining chemotherapy and oxygen intra-tumoral distribution, we investigated the role of DLL4 expression in tumour vasculature in the efficacy of radio-chemotherapy for HNSCC patients. Materials and methods Sixty-five biopsy specimens from HNSCC patients with inoperable disease were immunohistochemically examined using anti-CD31 (pan-endothelial cell marker) and anti-DLL4 antibodies and the vascular density (VD) was recorded. Patients were treated with platinum based hypofractionated accelerated conformal radiotherapy. The median follow-up period was 24 months (4–80 months).
M. I. Koukourakis (&) Department of Radiotherapy/Oncology, Democritus University of Thrace, PO BOX 12, 68100 Alexandroupolis, Greece e-mail: [email protected] A. Giatromanolaki E. Sivridis Department of Pathology, Democritus University of Thrace, 68100 Alexandroupolis, Greece e-mail: [email protected] K. C. Gatter Department of Pathology, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford OX3 9DS, UK e-mail: [email protected] A. L. Harris Cancer Research UK, Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 7LJ, UK e-mail: [email protected]
Results Using the 33rd and 66th percentiles cases were grouped in three categories of low, medium and high CD31? or DLL4? VD. The percentage of vessels expressing DLL4 (DLL4-ratio) ranged from 17 to 100 % (mean 71 %), showing substantial variation among cases. In accordance with previous published studies, a biphasic pattern of association of CD31? VD with poor outcome was noted. Cases with a medium VD had a significantly better local relapse free survival (LRFS) compared to cases of high VD (p = 0.0005, HR 0.15) and of low VD (p = 0.02, HR 0.28). High DLL4/CD31 ratio defined improved LRFS in both these subgroups of poor prognosis. Conclusions The expression of DLL4 is associated with reduced radio-resistance, presumably by reducing hypoxia and improving chemotherapy accessibility. Using the combination of CD31 and DLL4 staining, a classification is suggested so that HNSCCs are categorized in sub-groups to be targeted by different anti-angiogenic and hypoxia targeting agents. Keywords CD31 DLL4 Angiogenesis Head-neck cancer Radiotherapy
Introduction Tumor angiogenesis is an essential process for cancer cell growth, invasion and metast
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